CN114591338B - 一种Syk和VEGFR2双靶点抑制剂的制备方法及其用途 - Google Patents
一种Syk和VEGFR2双靶点抑制剂的制备方法及其用途 Download PDFInfo
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Abstract
本申请涉及一种Syk和VEGFR2双靶点抑制剂的制备方法及其用途。具体地,本申请涉及一种用于制备式(I)化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物的方法,所述方法不需要优先对吡唑硼酸酯进行保护并且能够顺利进行后续Suzuki反应以制备Syk和VEGFR2双靶点抑制剂。
Description
技术领域
本申请属于医药合成领域,具体地,涉及一种脾酪氨酸激酶(Syk)和血管内皮生长因子2(VEGFR2)双靶点抑制剂的制备方法及其用途。
背景技术
Syk为非受体酪氨酸激酶,其在多种细胞类型中的免疫受体-介导的和整联蛋白-介导的信号转导中起着重要作用,包括B细胞、巨噬细胞、单核细胞、肥大细胞、嗜酸粒细胞、嗜碱粒细胞、嗜中性粒细胞、树突细胞、T细胞、自然杀伤细胞、血小板和破骨细胞。本申请中描述的免疫受体包括典型的免疫受体和免疫受体样分子。典型的免疫受体包括B-细胞和T-细胞抗原受体以及多种免疫球蛋白受体(Fc受体)。免疫受体样分子为结构上与免疫受体相关的或参与类似信号转导路径,且其主要涉及于非适应性免疫功能(包括嗜中性粒细胞活化、自然杀伤细胞识别和破骨细胞活性)。整联蛋白是细胞表面受体,其在白细胞粘连和先天和后天免疫性二者的活化中起着关键作用。
VEGFR2,也称为KDR或Flk-1,被确定为VEGF和VEGFC的受体,是内皮细胞祖细胞的早期标记物,其表达仅限于体内内皮细胞。VEGFR2被证明是血管生成和病理状况(例如癌症和糖尿病性视网膜病)发展的主要信号转导者。已有研究表明表明,抗VEGF可以对促炎因子的表达和激活产生抑制作用,从而减轻眼表炎症。VEGFR2通过其强大的酪氨酸激酶活性转导血管生成的主要信号。但是,与其他代表性的酪氨酸激酶受体不同,VEGFR2并不使用Ras途径作为主要的下游信号传导,而是使用磷脂酶C蛋白激酶C途径来表达有丝分裂原激活蛋白(MAP)激酶激活和DNA合成。因此,抑制VEGFR2活性及其下游信号传导是治疗涉及血管生成及炎症等疾病的重要靶标。
因此,Syk和VEGFR-2活性的抑制可用于治疗变态反应性疾病、自身免疫性疾病和炎性疾病,包括但不局限于干眼症及过敏性结膜炎、视网膜炎性疾病,年龄相关性黄斑变性(AMD)、增殖性糖尿病视网膜病变(PDR)和早产儿视网膜病变(ROP)、癌症、类风湿性关节炎、肾小球肾炎、多发性血管炎、特发性血小板减少性紫癜(ITP)、重症肌无力、变应性鼻炎、慢性阻塞性肺病(COPD)、成人呼吸窘迫综合征(ARD)和哮喘等。
本申请人的发明名称为“作为Syk和VEGFR2双靶点抑制剂的1H-吡唑衍生物及应用”的PCT国际专利申请WO2021169958A1中公开了一种针对Syk和VEGFR2的双靶点抑制剂,并且进一步公开了该类双靶点抑制剂的多种制备方法,包括例如:
制备方法1:
制备方法2:
在该PCT国际专利申请的Suzuki偶联反应中,所采用的钯催化剂体系为以Pd(dppf)Cl2为前体的催化体系;为保证该钯催化剂体系在Suzuki反应中的反应活性,吡唑硼酸酯需要先采用Boc或者SEM基团进行保护以防止与催化剂发生络合;偶联反应结束之后,保护基Boc或者SEM在对应的条件下被移除,得到化合物1-6的粗品。在该工艺中,Boc保护的吡唑硼酸酯需要进行额外的柱层析纯化,以防止上保护基的反应中的副产物残留会影响Suzuki反应的催化体系活性。
因此,正在寻求一种不需要优先对吡唑硼酸酯进行保护并且能够顺利进行后续Suzuki反应以制备Syk和VEGFR2双靶点抑制剂的方法。
发明内容
本发明的目的在于克服现有的制备Syk和VEGFR2双靶点抑制剂的方法存在需要对作为反应原料的吡唑硼酸酯进行保护以防止与催化剂发生络合并还需要额外的特定步骤来去除保护基团的缺陷,提供一种不需要优先对吡唑硼酸酯进行保护并且能够顺利进行后续Suzuki反应以制备Syk和VEGFR2双靶点抑制剂的方法。
在第一方面,本申请提供了一种用于制备式(I)化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物的方法,
其中,
R1和R2中的一者为H,且另一者为吡唑基;
R3和R4各自独立地选自由H、F、Cl、Br、I、OH、NH2、CN、C1-3烷基和C1-3烷氧基组成的组,所述C1-3烷基和C1-3烷氧基任选被1、2或3个卤素取代;
T1为CH或N;
R5和R6各自独立地选自由H、F、Cl、Br、I、OH和C1-3烷基组成的组,所述C1-3烷基任选被1、2或3个卤素取代;或者,R5和R6与它们共同连接的碳原子一起形成氧杂环丁烷基;
R8为H或-C(=O)-C1-3烷基;以及
n为1或2;并且
其中,所述方法包括以下步骤:
在存在钯催化体系和SEM-Cl(2-氯甲氧基乙基三甲基硅)的反应条件下,使式(II)化合物:
其中,
R9和R10中的一者为H,且另一者为卤素;
与式(III)化合物:
反应,
所述反应结束后,向反应体系中加入脱保护剂以去除保护SEM基团,以得到所述式(I)化合物。
在本发明的方法中,Suzuki反应中采用的是未保护的吡唑硼酸酯,并且选用SEM-Cl为配体;未保护的吡唑基团对此钯催化体系活性没有影响,Suzuki反应可以顺利进行;用未保护的吡唑硼酸酯进行Suzuki反应后直接向反应体系中加入脱保护剂即可以直接生成式(I)化合物的粗品,即在一个反应体系中完成合成,无需进行转移。
另外,本申请的反应原料化合物(例如,式(II)或(III)化合物)可按有机合成领域技术人员已知的多种方式制备,例如也可以参见本申请人的PCT国际专利申请WO2021169958A1中公开的方法来进行。此外,本领域技术人员可以参照本申请具体实施例的具体化合物的合成路线,对反应原料和反应条件进行适当调整而得到其它化合物的合成方法。
在本发明的一个实施方式中,
所述式(II)化合物可以通过如下反应方程式制备得到:
其中,R3、R4、R9、R10、T1、D1、n如上所定义。
更具体地,例如,在本发明的一个优选实施方式中,所述式(II)化合物可以通过如下反应方程式制备,但不限于此:
其中,反应条件A可以为:EtOAc(乙酸乙酯)、N,N-二甲基苯胺、POCl3(三氯氧磷);反应条件B可为:DIPEA(N,N-二异丙基乙胺乙胺)、DMSO(二甲基亚砜)。
另外,在本发明的一个优选实施方式中,
在本发明的另一个优选实施方式中,
所述R3和R4可以各自独立地选自由H、F、Cl、Br、I、OH、NH2、CN、甲基和甲氧基组成的组。
在本发明的另一个优选实施方式中,
所述R5和R6可以各自独立地选自由H、F、Cl、Br、I、OH和甲基组成的组。
在本发明的另一个优选实施方式中,
在本发明的另一个优选实施方式中,
在本发明的另一个优选实施方式中,
所述R8可以为H或-C(=O)-CH3。
在本发明的另一个优选实施方式中,
在本发明的另一个优选实施方式中,
在本发明的另一个优选实施方式中,
所述钯催化体系可以包含Pd(dppf)Cl2([1,1'-双(二苯基膦基)二茂铁]二氯化钯)、K2CO3(碳酸钾)、DIPEA(N,N-二异丙基乙胺)、2-甲基四氢呋喃和H2O。
在本发明的另一个优选实施方式中,
所述脱保护剂可以包含乙二胺和四丁基氟化铵(TBAF)的四氢呋喃溶液。
在本发明的另一个优选实施方式中,
所述式(II)化合物与所述式(III)化合物的重量比可以为1:0.3-0.8(例如1:0.4、1:0.45、1:0.5、1:0.53、1:0.57、1:0.6或1:0.7等),优选1:0.5-0.6;和/或所述式(II)化合物与所述钯催化体系中的钯催化剂的重量比可以为1:0.05-0.2(例如1:0.07、1:0.08、1:0.09、1:0.1、1:0.12、1:0.15、1:0.18等),优选1:0.08-0.15。
在本发明的另一个优选实施方式中,
所述反应可以在60-100℃(例如65℃、70℃、75℃、80℃、85℃、90℃或95℃等)、优选85-95℃(例如87℃、90℃或92℃等)的温度下进行。
在本发明的另一个优选实施方式中,
所述方法还可以包括对所述式(I)化合物的纯化步骤。所述纯化步骤可以使用本领域中常见的各种纯化手段,例如可以包括漂洗、蒸馏、过滤、离心和重结晶等等,只要能够达到提高产物中所述式(I)化合物的浓度即可。
为了简明起见,后文所述“式(I)化合物”或“本申请的化合物”也可以涵盖式(I)化合物的任意同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物。
术语“光学异构体”意指,当化合物具有一个或更多个手性中心时,每个手性中心可以存在R构型或S构型,由此构成的各种异构体为光学异构体。光学异构体包括所有的非对映异构体、对映异构体、内消旋体、外消旋体或其混合物形式。例如,通过手性色谱柱或通过手性合成可以分离光学异构体。
术语“几何异构体”意指,当化合物中存在双键时,该化合物可以存在顺式异构体、反式异构体、E型异构体和Z型异构体。几何异构体包括顺式异构体、反式异构体、E型异构体、Z型异构体或其混合物形式。
术语“互变异构体”指因分子中某一原子在两个位置迅速移动而产生的异构体。本领域技术人员可以理解:互变异构体之间可以互相转变,在某一状态下可能会达到一种平衡状态而共存。
除非另有指明,本文提到“式(I)化合物”或“本发明的化合物”时也涵盖该化合物中任一个原子被其同位素原子代替而得到的同位素标记化合物。本发明包括式(I)化合物的所有药学上可接受的同位素标记化合物,其中,一个或者多个原子被具有与通常在自然界中所发现的原子相同原子序数但是不同原子质量或者质量数的原子所替换。
适用于包含在本发明的化合物中的同位素的实例包括氢的同位素,诸如2H(D)和3H(T),碳的同位素,诸如11C、13C和14C,氯的同位素,诸如35Cl和37Cl,氟的同位素,诸如18F,碘的同位素,诸如123I和125I,氮的同位素,诸如13N和15N,氧的同位素,诸如15O、17O和18O,以及硫的同位素,诸如35S。
式(I)的同位素标记化合物一般可以通过本领域技术人员已知的常规技术或者通过使用合适的同位素标记试剂代替先前使用的非标记试剂以类似于在本文所附的实例和制备中所描述的方法,来进行制备。
式(I)化合物可以药学上可接受的盐的形式存在,比如,式(I)化合物的酸加成盐和/或碱加成盐。除非另有指明,否则本文所用的“药学上可接受的盐”包括可出现于式(I)化合物内的酸加成盐或碱加成盐。
式(I)化合物的药学上可接受的盐类包括其酸加成盐和碱加成盐。适当的酸加成盐是由形成无毒性盐的酸所形成的。其实例包括但不限于:乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己胺磺酸盐、乙二磺酸盐、甲酸盐、反丁烯二酸盐、葡萄庚糖酸盐、葡萄糖酸盐、葡萄糖醛酸盐、六氟磷酸盐、2-(4-羟苄基)苯甲酸盐、氢氯化物/氯化物、氢溴化物/溴化物、氢碘化物/碘化物、2-羟乙磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘酸盐、2-萘磺酸盐、烟碱酸盐、硝酸盐、乳清酸盐、草酸盐、十六酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、葡萄糖二酸盐、硬脂酸盐、水杨酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。适当的碱加成盐是由形成无毒性盐的碱所形成的。其实例包括但不限于:铝、精氨酸、钙、胆碱、二乙胺、二乙醇胺、甘氨酸、赖氨酸、镁、葡甲胺、乙醇胺、钾、钠、氨丁三醇和锌盐。还可形成酸和碱的半盐,例如半硫酸盐和半钙盐。关于合适的盐的综述,参见Handbook of Pharmaceutical Salts:Properties,Selection and Use by Stahland Wermuth(Wiley-VCH,2002)。用于制备本文中所述的化合物的药学上可接受的盐的方法是本领域技术人员已知的。
本发明的某些化合物可以以非溶剂化形式以及溶剂化形式(包括水合形式)存在。一般而言,式(I)化合物无论以溶剂化形式存在或以未溶剂化形式存在,其都包括在本发明的范围内。
本发明的某些化合物可以不同晶型或不定型形式存在,无论以何种形式存在,式(I)化合物都包括在本发明的范围内。
为了避免歧义,下面对本文中所使用的术语给出定义。除非另有说明,本文所用术语的含义如下。
术语“药学上可接受的”是指相应的化合物、载体或分子适于给予人。优选地,该术语是指由管理机构例如CFDA(中国)、EMEA(欧洲)、FDA(美国)等任意国家管理机构认证的用于哺乳动物优选人。
“前体药”是指通过与酶、胃酸等在生理条件下在活体内例如通过各自在酶催化下进行的氧化、还原、水解等反应转化为本发明化合物的衍生物。
“代谢物”是指在细胞或有机体优选人中源自本发明任意化合物的所有分子。
在本文中使用时,术语“被取代”是指基团中的一个或多个(优选1至5个,更优选1至3个)氢原子独立地被相应数目的取代基所代替。
在本文中使用时,术语“各自独立地”是指当取代基的个数超过一个时,这些取代基可以相同也可以不同。
在本文中使用时,术语“任选”或“任选地”表示其所描述的事件可以发生或不发生。例如,一个基团“任选地被取代”表示:该基团可以是未被取代的,也可以是被取代的。
在本文中使用时,术语“烷基”是指饱和的脂族烃,包括直链及支链。在一些实施方式中,烷基基团具有1-8个、或1-6个、或1-3个碳原子。例如,术语“C1-8烷基”是指具有1-8个碳原子的直链或支链原子团。术语“C1-8烷基”在其定义中包括术语“C1-6烷基”、“C1-C3烷基”和“C1-C4烷基”。烷基的实例包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、2-戊基、3-戊基、异戊基、新戊基、(R)-2-甲基丁基、(S)-2-甲基丁基、3-甲基丁基、2,3-二甲基丙基、2,3-二甲基丁基、己基等。烷基基团可任选地被一或多个(例如,1至5个)适当的取代基所取代。
在本文中使用时,术语“卤代烷基”是指具有一或多个卤素取代基的烷基基团(至多全卤代烷基,即,烷基基团的每个氢原子均被卤素原子所取代)。例如,术语“C1-6卤代烷基”是指具有一或多个卤素取代基的C1-6烷基基团(至多全卤代烷基,即,烷基基团的每个氢原子均被卤素原子所取代)。另举一例,术语“C1-4卤代烷基”是指具有一或多个卤素取代基的C1-4烷基基团(至多全卤代烷基,即,烷基基团的每个氢原子均被卤素原子所取代);术语“C1-3卤代烷基”是指具有一或多个卤素取代基的C1-3烷基基团(至多全卤代烷基,即,烷基基团的每个氢原子均被卤素原子所取代);且术语“C1-2卤代烷基”是指具有一或多个卤素取代基的C1-2烷基基团(即,甲基或乙基)(至多全卤代烷基,即,烷基基团的每个氢原子均被卤素原子所取代)。再另举一例,术语“C1卤代烷基”是指具有1、2或3个卤素取代基的甲基基团。卤代烷基基团的例子包括:CF3、C2F5、CHF2、CH2F、CH2CF3、CH2Cl等。
本文中,与取代基个数、碳原子个数、环原子个数相关的数目范围表示该范围内所有整数的逐个列举,而范围仅是作为一种简化的表示法。例如:“1-4个取代基”表示1、2、3或4个取代基;“3-8个环原子”表示3个、4个、5个、6个、7个或8个环原子。因此,与取代基个数、碳原子个数、环原子个数相关的数目范围也涵盖其任意一个子范围,且每一个子范围也视为被本文公开。
在第二方面,本申请提供了一种药物组合物,其包含式(I)化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物,以及药学上可接受的载体。
药学上可接受的载体可以是有机或无机惰性载体材料,例如,合适的载体包括水、明胶、阿拉伯树胶、乳糖、淀粉、硬脂酸镁、滑石、植物油、聚亚烷基二醇、凡士林、甘露醇、纤维素、纤维素衍生物、糖精钠、葡萄糖、蔗糖、碳酸镁、盐水、甘油、乙醇等。此外,药物组合物还可含有其他药物添加剂,例如调味剂、防腐剂、稳定剂、乳化剂、缓冲剂、稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂等。
本申请的药物组合物的剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、丸剂、栓剂、膜剂、贴片、气雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。本申请的药物组合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
在一些实施方式中,所述药物组合物的剂型选自片剂、颗粒剂、散剂、糖浆剂、吸入剂和注射剂。
用于口服的固体剂型可以包括胶囊、片剂、丸剂、粉末和颗粒。在这种固体剂型中,将活性化合物与至少一种惰性赋型剂(或载体)(例如,柠檬酸钠或磷酸二钙)混合,其中还可以包括:(a)填料或混合剂(例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸);(b)粘结剂(例如,羧基甲基纤维素、褐藻酸酯、凝胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯树胶);(c)保湿剂(例如,丙三醇);(d)崩解剂(例如,琼脂-琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、某些合成的硅酸酯、碳酸钠);(e)溶液阻滞剂(例如,石蜡);(f)吸收促进剂(例如,季铵化合物);(g)润湿剂(例如,十六烷醇和单硬脂酸丙三醇酯);(h)吸附剂(例如,高岭土和斑脱土)和(i)润滑剂(例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠)或其混合物混合。
适于肠胃外施用的制剂例如注射剂可以包括适于注射的水性和非水性等渗无菌溶液,以及水性和非水性无菌混悬剂。本文提供的肠胃外制剂任选地包含在单位剂量或多剂量密封容器(例如安瓿)中,并且可以储存在仅需要于即将使用前添加无菌液体载体(例如注射用水)的冷冻干燥(冻干)条件下。用于重构药物组合物(例如在注射前)的合适稀释剂的实例包括抑菌性注射用水、5%葡萄糖水溶液、磷酸盐缓冲盐水、林格氏(Ringer's)溶液、盐水、无菌水、去离子水及其组合。
喷雾剂可含有赋形剂,如乳糖、滑石、硅酸、氢氧化铝、硅酸钙和聚酰胺粉剂,或这些物质的混合物。喷雾剂可另外含有常规推进剂,例如氯氟烃和挥发性未经取代的烃,例如丁烷和丙烷。吸入剂可包含赋形剂如乳糖,或是包含如聚环氧乙烷-9-月桂基醚,甘氨胆酸盐和脱氧胆酸盐的含水溶液,或是油性溶液以鼻滴剂或喷雾,或凝胶形式施用。
本申请的化合物在其药物组合物中的含量可以根据实际需要(例如剂型、施用方式、施用对象等)进行调整,例如为0.1-95重量%,例如1-95重量%,5-90重量%,10-80重量%等。
具体地,本申请的药物组合物中可以特别地包含0.01-10g(例如0.05g、0.1g、0.5g、1g或5g等)的本申请的化合物。
在第三方面,本申请提供了式(I)化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物在制备用于在有需要的受试者中治疗或预防由Syk和VEGFR2介导的疾病或病症的作为Syk和VEGFR2双靶点抑制剂的药物中的用途。式(I)化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物可以用于在有需要的受试者中治疗或预防由Syk和VEGFR2介导的疾病或病症。
本申请使用的术语“受试者”是指可潜在地从用式(I)化合物进行的治疗中受益的任何人类或非人类生物体。示例性受试者包括任何年龄的人类或哺乳动物。优选地,所述受试者是人。
本文使用的术语“治疗”包括在哺乳动物、尤其人类中治疗疾病或病症且包括:(a)抑制感染、疾病或病症,即遏制或延缓感染、疾病或病症的发展;(b)缓解感染、疾病或病症,即引起疾病或病症的消退,和/或(c)感染、疾病或病症的治愈。
本文使用的术语“预防”包括在哺乳动物、尤其人类中进行预防性疗法以旨在降低感染、疾病或病症发生的可能性。可以根据与一般群体相比感染或患有疾病或病症的风险增加为因素来选择接受预防性疗法的患者。“预防”可以包括对尚未呈现感染或临床病况的受试者进行处置,和预防相同或类似感染或临床病况的第二次出现。
在一些实施方式中,所述由Syk和VEGFR2介导的疾病或病症可以选自变态反应性疾病、自身免疫性疾病和炎性疾病,如干眼症及过敏性结膜炎、视网膜炎性疾病、年龄相关性黄斑变性(AMD)、增殖性糖尿病视网膜病变(PDR)和早产儿视网膜病变(ROP)、类风湿性关节炎、肾小球肾炎,多发性血管炎、特发性血小板减少性紫癜(ITP)、重症肌无力、变应性鼻炎、慢性阻塞性肺病(COPD)、成人呼吸窘迫综合征(ARD)和哮喘。在另一些实施方式中,所述疾病或病症是癌症。
在一些实施方式中,本发明化合物可以通过口服、肠胃外、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、经肺、经呼吸道、经阴道、经直肠、腹膜内、病灶内、病灶周围等途径施用。
“治疗有效量”是指本申请化合物当单独或组合给药时有效治疗或预防由Syk和VEGFR2介导的疾病或病症的量。
具体施用剂量将取决于施用途径、疾病的严重程度、患者的年龄和体重,以及主治医师在确定最适合特定患者的个体方案和剂量水平时通常考虑的其他因素。例如,本申请的化合物的日剂量可以特别地为0.001-150mg/kg体重(例如0.1mg/kg体重、1mg/kg体重、10mg/kg体重或100mg/kg体重等)。
具体的施用频率可以由相关领域的技术人员确定,例如为1天1次、2天1次、3天1次、4天1次、5天1次、6天1次、1天2次、1天3次等。
本领域技术人员能够理解,在本申请的一个方面中描述的定义和优选项同样适用于其他方面。本领域技术人员能够明了本申请各个方面的实施方式可以以各种方式组合,而不偏离本申请的主题和思想,这些组合也包括在本申请的范围内。
具体实施方式
下面进一步结合实施例来阐述本发明;但这些实施例并不限制本发明的范围。除非另有声明,各实施例中所用的所有反应物均从商业途径获得;合成实验和产物分析检测中所用仪器设备等均为有机合成中通常使用的常规仪器和设备。
实施例
合成路线如下所示:
1)化合物2-3的制备
步骤1的原料及投料量如下表1所示。
表1
向50L反应釜中加入11.0L二甲基亚砜,开启搅拌,转速为150rpm,温度显示为内温20℃。依次加入833.0g化合物2-2、1510.0g N,N-二异丙基乙胺和1100.0g化合物2-1。设置外部温度为100℃,在内温95~100℃下搅拌24小时。
取反应液HPLC检测,HPLC显示化合物2-1剩余小于3%。关闭加热,将反应液冷却至20~25℃。将反应液缓慢倒入30.0L搅拌的水中。控制内部温度为10~15℃条件,搅拌0.5小时,转速为100rpm。保持内温10~15℃条件下,减压抽滤,收集滤饼重新投入反应釜中,向釜中加入15.0L异丙醇。设置外部温度为85℃,在内温80~85℃下搅拌1小时。保持内温80~85℃条件下,进行减压抽滤,滤饼再用4.0L异丙醇洗涤。收集滤饼放置在真空干燥箱内,在50~55℃,-0.1Mpa的条件下真空干燥12小时,得到1300.0g化合物2-3,收率为79.0%。
2)化合物2-5的制备
步骤2的原料及投料量如下表2所示。
表2
向50L反应釜中加入8.0L 2-甲基四氢呋喃,开启搅拌,转速为150rpm,设置外部温度为5~10℃。依次加入1070.0g化合物2-4、764.0g碳酸钾和711.7g N,N-二异丙基乙胺。在内温5~10℃时用恒压滴液漏斗滴加1200.0g 2-氯甲氧基乙基三甲基硅,滴加完成后,控制内部温度为15~20℃的条件下,搅拌3小时。
取反应液HPLC检测,谱图显示化合物2-4剩余小于1.0%。继续向反应釜中加入7.2L2-甲基四氢呋喃、3.8L水、1900.0g化合物2-3、1376.0g碳酸钾和164.0gPd(dppf)Cl2。向反应釜中通入氮气置换20分钟后设定外部温度为85℃。内温在80~85℃下搅拌16小时。取样HPLC检测化合物2-3已完全转化,冷却至内温15~20℃,在搅拌下向反应釜中缓慢加入10.0L水和40.0L正庚烷。保持内温15~20℃搅拌20分钟后减压过滤,滤饼放置在真空干燥箱内,在50~55℃,-0.1MPa条件下真空干燥20小时后得到2800.0g粗品化合物2-5。
向50L反应釜中加入28.0L2-甲基四氢呋喃,搅拌下加入2800.0g粗品化合物2-3。开启加热,设定外部温度为75~80℃,搅拌1小时后,粗品化合物2-3完全溶清,然后加入820.0g CPL型活性炭,在内温75~80℃下搅拌16小时。70~80℃下经2~4cm厚硅藻土层趁热过滤,收集滤液。
将收集的滤液重新倒回反应釜中,继续加入560.0g CPL型活性炭。在内温75~80℃下搅拌16小时。保持温度在70~80℃下,经2~4cm厚硅藻土层趁热过滤,收集滤液,并在40~45℃、-0.1MPa的条件下,减压浓缩至滤液总体积为15升左右,将该滤液重新倒回反应釜中,并分批加入30.0L正庚烷,在15~20℃下搅拌1小时,减压抽滤得到滤饼,滤饼真空干燥(40~50℃、-0.1MPa)20小时至恒重,得1650.0g化合物2-3,收率为68.0%。
3)化合物2-6的制备
步骤3的原料及投料量如下表3所示。
表3
向50L反应釜中加入20.0L 1mol/L TBAF四氢呋喃溶液,开启搅拌,转速为150rpm。依次加入2000.0g化合物2-3和222.0g乙二胺。在内温65~72℃下搅拌16小时。
取反应液HPLC检测,谱图显示化合物2-3剩余小于1%,并且保持温度在50~55℃条件下,向反应釜中加入16.0L四氢呋喃,内温控制在39~42℃下搅拌2小时,然后在15~20℃下继续搅拌2小时。减压抽滤,将滤饼重新倒回釜中,加入25.0L水和12.5L乙醇,在内温65~70℃下搅拌16小时。保持内温65~70℃下减压热过滤,收集滤饼,真空干燥(50~55℃、-0.1MPa)12小时至恒重得1270.3g化合物2-6粗品,收率为84.0%。
4)化合物2-6的纯化
步骤4的原料及投料量如下表4所示。
表4
向50L反应釜中加入15.0L乙醇和25.0L去离子水,分批加入1200.0g化合物2-6粗品。设置外部温度为72℃,在内温65~72℃下搅拌48小时。
保持内温在65~72℃条件下,趁热减压过滤,收集滤饼并重新倒回反应釜中,并向釜中加入40.0L去离子水。控制内温在65~75℃下搅拌16小时。保持内温65~75℃下,进行减压抽滤,收集滤饼真空干燥(40~50℃、-0.1MPa)20小时至恒重得1140.0g化合物2-6,收率为95.0%。
Claims (19)
1.一种用于制备式(I)化合物或其药学上可接受的盐的方法,
其中,
R1和R2中的一者为H,且另一者为吡唑基;
R3和R4各自独立地选自由H、F、Cl、Br、I、OH、NH2、CN、C1-3烷基和C1-3烷氧基组成的组,所述C1-3烷基和C1-3烷氧基任选被1、2或3个卤素取代;
T1为CH或N;
R5和R6各自独立地选自由H、F、Cl、Br、I、OH和C1-3烷基组成的组,所述C1-3烷基任选被1、2或3个卤素取代;或者,R5和R6与它们共同连接的碳原子一起形成氧杂环丁烷基;
R8为H或-C(=O)-C1-3烷基;以及
n为1或2;并且
其中,所述方法包括以下步骤:
在存在钯催化体系和SEM-Cl的反应条件下,其中所述钯催化体系包含2-甲基四氢呋喃和H2O,使式(II)化合物:
其中,
R9和R10中的一者为H,且另一者为卤素;
与式(III)化合物:
反应,
所述反应结束后,向反应体系中加入脱保护剂以去除保护SEM基团,以得到所述式(I)化合物。
3.根据权利要求1所述的方法,其中,所述R3和R4各自独立地选自由H、F、Cl、Br、I、OH、NH2、CN、甲基和甲氧基组成的组。
4.根据权利要求1所述的方法,其中,所述R5和R6各自独立地选自由H、F、Cl、Br、I、OH和甲基组成的组。
7.根据权利要求1所述的方法,其中,所述R8为H或-C(=O)-CH3。
10.根据权利要求1-9中任一项所述的方法,其中,所述钯催化体系还包含Pd(dppf)Cl2、K2CO3和DIPEA。
11.根据权利要求1-9中任一项所述的方法,其中,所述脱保护剂包含乙二胺和四丁基氟化铵的四氢呋喃溶液。
12.根据权利要求1-9中任一项所述的方法,其中,所述式(II)化合物与所述式(III)化合物的重量比为1:0.3-0.8;和/或所述式(II)化合物与所述钯催化体系中的钯催化剂的重量比为1:0.05-0.2。
13.根据权利要求12所述的方法,其中,所述式(II)化合物与所述式(III)化合物的重量比为1:0.5-0.6。
14.根据权利要求12所述的方法,其中,所述式(II)化合物与所述钯催化体系中的钯催化剂的重量比为1:0.08-0.15。
15.根据权利要求1-9中任一项所述的方法,其中,所述反应在60-100℃的温度下进行。
16.根据权利要求15所述的方法,其中,所述反应在85-95℃的温度下进行。
17.根据权利要求1-9中任一项所述的方法,其中,所述方法还包括对所述式(I)化合物的纯化步骤。
19.根据权利要求18所述的方法,其中,步骤1的反应条件包括EtOAc、N,N-二甲基苯胺和POCl3;并且步骤2的反应条件B包括DIPEA和DMSO。
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